NAOMI TAYLOR & MARC SITBON

The supposition that different cytokines are required for commitment to distinct hematopoietic lineages is an “accepted wisdom” but the possibility that nutrient entry plays a role in this process/choice was not considered until very recently. Based on the discovery by our teams that the Glut1 glucose transporter is a receptor for the human T cell leukemia virus (HTLV) (Manel et al., Cell, 2003), we generated HTLV receptor-binding domain (RBD) fusion proteins allowing us to monitor and study the role of Glut1 during erythropoiesis. Notably, we found that Glut1 is actually not expressed on erythrocytes of all species, as assumed by the prevalent dogma up to 3 years ago, but is restricted to those few mammals unable to synthesize ascorbic acid from glucose (higher primates, guinea pigs and fruit bats). In these species, erythroid Glut1 (eGlut1), >200,000 molecules / cell, preferentially transports an oxidized form of vitamin C, L-dehydroascorbic acid, likely providing a compensatory mechanism for the lost ability to synthesize this essential metabolite (Cell 132: 2008; Cell 137: 2009). Furthermore, we found that in all mammals tested, Glut1 is expressed during neonatal erythropoiesis; a discovery opening up new paradigms in that subsequent glucose uptake in erythrocytes is mediated by Glut4, an insulin-sensitive transporter never before considered to be expressed on erythrocytes (Blood 112: 2008; Curr Hematol 16: 2009).

These studies, as well as the lack of reliable antibodies recognizing exofacial nutrient transporters, motivated our generation of a collection of RBDs as specific nutrient transporter ligands, which will make it possible for the first time to directly detect key transporters including Glut1, the ASCT2/SCL1A5 glutamine transporter, the PiT1 and PiT2 phosphate transporters, the THTR1 thiamine transporter, the hRFT1 riboflavin transporter, and the hFLVCR heme exporter in erythroid differentiation. Establishing the global network of nutrient transporters expressed during early and terminal erythroid differentiation will facilitate collaborative studies aimed at identifying the role of each identified transporter in normal and dysregulated erythropoiesis as well as in the « making of red cells ». This characterization together with subsequent investigations of metabolite uptake/efflux will reveal the functions of individual transporters in orienting erythroid cell survival and differentiation.

Surface Glut1 expression was monitored in mammals defective in AA synthesis and those capable of synthesizing this essential carbohydrate. Profiles are shown in the top and bottom left panels, respectively. Primates of the Haplorrhini suborder, including long-tailed macaques, rhesus monkeys, and baboons, are defective in AA synthesis while lower primates from the Strepsirrhini suborder, comprising lemurs, are capable of synthesizing AA. The presence of Glut1 in AA-defective mammals allows the transport of DHA that is immediately reduced to AA. In AA-synthesizing mice (as well as dogs (Ogawa, 2008)), GLUT4 facilitates the transport of glucose (right panels). The identity of the glucose transporter expressed on adult erythrocytes in other AA-synthesizing species remains to be determined (from Montel-Hagen et al. 2008 and 2009).

Expertise

Scientific direction for the Montpellier RIO/IBiSA flow cytometry platform with state of the art cell sorting and cell analysis equipment.

In partnership with L. d’Auriol and V. Petit, M. Sitbon has created METAFORA Biosystems, a spin off biotech member of GR-Ex, incubated by the Business and Innovation Centre (BIC) of Montpellier Agglomération, and successive laureate of the OSEO «2010 Emerging» and «2012 Creation-Development» awards. The expertise of the company stems from the capacity to generate and commercialize expression profiles of metabolite transporters at the cell surface.